Nasal delivery device

ABSTRACT

A delivery device ( 20, 22 ) for and a method of delivering a substance to the nasal airway ( 1 ) of a subject, in particular the posterior region of the nasal airway, the delivery device comprising: a closure unit for causing the closure of the oropharyngeal velum of the subject; and a delivery unit for delivering a gas flow entraining a substance to one of the nostrils of the subject at such a driving pressure as to flow around the posterior margin of the nasal septum and out of the other nostril of the subject, wherein the delivery unit comprises a nosepiece ( 30, 40, 58, 82, 102, 132 ) which includes an outlet through which the gas flow is in use delivered to the one nostril and a sealing member for sealing the one nostril to the outlet such as in use to prevent the escape of the gas flow through the one nostril.

RELATED APPLICATION DATA

This application is a continuation of application Ser. No. 09/700,532,filed Nov. 15, 2000, now U.S. Pat. No. 6,715,485, which is a nationalphase of International Application No. PCT/IB00/00273, filed Mar. 3,2000, and published in the English language under Publication No. WO00/51672, both of which applications are hereby incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates to a delivery device for and a method ofdelivering a substance, in particular one of a liquid, as a suspensionor solution, or a powder containing a medicament, especially a topicalpharmaceutical, a cleansing agent, or an irrigating agent, as a liquid,preferably combined with a cleansing agent, to the nasal airway of asubject. In particular, the present invention relates to the delivery ofmedicament to and the irrigation of the nasal mucosa, the anteriorregion of nasopharynx, the paranasal sinus ostia, the tubal ostia of theauditory tubes, the sinus tubes, the auditory tubes, the tympaniccavities and the paranasal sinuses.

BACKGROUND

Referring to FIG. 1, the nasal airway 1 comprises the two nasal cavitiesseparated by the nasal septum, which airway 1 includes numerous ostia,such as the paranasal sinus ostia 3 and the tubal ostia 5, olfactorycells and is lined by the nasal mucosa. The nasal airway 1 cancommunicate with the nasopharynx 7, the oral cavity 9 and the lowerairway 11, with the nasal airway 1 being in selective communication withthe anterior region of the nasopharynx 7 and the oral cavity 9 byopening and closing of the oropharyngeal velum 13. The velum 13, whichis often referred to as the soft palate, is illustrated in solid line inthe closed position, as achieved by providing a certain positivepressure in the oral cavity 9, such as achieved on exhalation throughthe oral cavity 9, and in dashed line in the open position.

There are many nasal conditions which require treatment. One suchcondition is nasal inflammation, specifically rhinitis, which can beallergic or non-allergic and is often associated with infection andprevents normal nasal function. By way of example, allergic andnon-allergic inflammation of the nasal airway can typically effectbetween 10 and 20% of the population, with nasal congestion of theerectile tissues of the nasal concha, lacrimation, secretion of waterymucus, sneezing and itching being the most common symptoms. As will beunderstood, nasal congestion impedes nasal breathing and promotes oralbreathing, leading to snoring and sleep disturbance. Worryingly, theincidence of such allergic and non-allergic inflammatory diseases isincreasing. Other nasal conditions include nasal polyps which arise fromthe paranasal sinuses, hypertrophic adenoids, secretory otitis media,sinus disease and reduced olfaction.

In the treatment of certain nasal conditions, the topical administrationof medicaments is preferable, particularly where the nasal mucosa is theprime pathological pathway, such as in treating or relieving nasalcongestion. Indeed, topical administration is advantageous in minimizingthe possible side effects of systemic administration. Medicaments thatare commonly topically delivered include decongestants, antihistamines,cromoglycates, steroids and antibiotics.

There are now an increasing number of adults and children who rely onpharmaceuticals to relieve symptoms associated with nasal conditions. Atpresent, among the known anti-inflammatory pharmaceuticals, topicalsteroids have been shown to have an effect on nasal congestion. Topicaldecongestants have also been suggested for use in relieving nasalcongestion. The treatment of hypertrophic adenoids and chronic secretoryotitis media using topical decongestants, steroids and anti-microbialagents, although somewhat controversial, has also been proposed.Further, the topical administration of pharmaceuticals has been used totreat or at least relieve symptoms of inflammation in the anteriorregion of the nasopharynx, the paranasal sinuses and the auditory tubes.

Aside from the delivery of medicaments, the irrigation of the nasalmucosa with liquids, in particular saline solutions, is commonlypracticed to remove particles and secretions, as well as to improve themucociliary activity of the nasal mucosa. These solutions can be used incombination with active pharmaceuticals.

Furthermore, medicaments are now increasingly systemically deliveredthrough the nasal pathway, the nasal pathway offering a goodadministration route for the systemic delivery of pharmaceuticals, suchas hormones, for example oxytocin, and antimigraine compositions, as thehigh blood flow and large surface area of the nasal mucosaadvantageously provides for rapid systemic uptake.

A variety of delivery systems have been developed to deliver substancesto the nasal airways of subjects.

Conventionally, spray bottles have been used to deliver amedicament-containing liquid or an irrigating liquid to the nasalairways of subjects. However, the distribution of the deliveredsubstance, in particular to the posterior region of the nasal airway, isless than ideal, especially in the cases of moderate and severe nasalobstruction. This poor distribution is often further exacerbated by asubject inhaling through the nasal airway during delivery, as is oftenprescribed, in an attempt to deliver the substance to the posteriorregion of the nasal airway. Indeed, an amount of the substance can bedrawn into the lungs or swallowed in each delivery, which could beproblematic in paediatric subjects if the medicament is a potentpharmaceutical, such as a steroid, which has to be administeredfrequently. In addition, the spray is frequently directed against thenasal septum which can undesirably lead to localized deposition.Further, the mechanical action of the delivery mechanism of the spraybottles can cause irritation and bleeding.

GB-A-408856 discloses a delivery device, which in one mode of use,apparently allows for the delivery of two separate air flows entrainingmedicament into respective ones of the nasal cavities of a subject. Thisdelivery device comprises a chamber containing a sponge saturated withmedicament, a mouthpiece connected to the chamber and first and secondnosepieces connected to the chamber. In one mode of use, the mouthpieceis taken in the mouth of a subject and the nosepieces fitted intorespective ones of the nostrils of the subject, and on exhalationthrough the mouthpiece separate air flows entraining medicament areapparently driven into the nasal cavities of the subject.

It is not seen, however, how this delivery device could functionproperly in this mode of use, since, as is now understood, the velum ofthe subject would close on exhalation through his or her mouth and henceclose the nasal airway, thereby preventing any significant air flow intothe nasal cavities.

WO-A-98/53869 discloses a delivery device for delivering a powdercontaining a medicament to the nasal mucosa in one of the nasal cavitiesof a subject. This device comprises a tubular section which contains ametered dose of powdered medicament. In use, the ends of the tubularsection are respectively located in the nostril of one of the nasalcavities and the mouth of a subject, and on exhalation by the subjectthrough his or her mouth the exhaled air entrains the powderedmedicament and delivers the same into the one nasal cavity, with theexhaled air backflowing out of the one nostril around the tubularsection. In one embodiment the tubular section includes a flexibleportion upstream of the dose of powdered medicament. The provision ofthis flexible portion allows the subject to close the tubular section ata point upstream of the medicament, such that, on release of the closedflexible portion during exhalation, a short explosive air flowentraining medicament is delivered into the one nasal cavity. In anotherembodiment the end of the tubular section located in the nostril can beshaped to act to locate the tubular section in a position in the nostrilwhich allows for the deposition of the powdered medicament on the nasalmucosa.

Whilst this delivery device is simple in construction, the operation ofthe device still does not provide for the effective delivery ofsubstances, in particular one of a liquid or powder containingmedicament, to the posterior region of the nasal airway, sincemedicament is delivered separately to each of the nasal cavities and theair flow into and out of each nasal cavity is through the same opening,namely the respective nostril, with the closed posterior region of therespective nasal cavity acting as a pressure reflecting surface whichcauses the exhaled air to backflow out of the one nostril before everadequately reaching the posterior region of the respective nasal cavity.Further, in providing a short explosive burst of air flow into one ofthe nasal cavities, it is not possible to achieve a sustained andcontrolled bidirectional air flow through the nasal cavities which hasbeen found necessary to deliver a substance effectively to the posteriorregion of the nasal airway.

For any substance to be delivered effectively to the nasal airway, it ishighly desirable that the administration is efficient and simple.However, there can be problems in attempting to achieve this goal. Inparticular, the pathological changes observed with nasal inflammationmake administration of substances, such as liquids or powders, tricky,particularly to the posterior region of the nasal airway and theposterior margins of the nasal structures. Indeed, as a consequence ofthe complex geometry of the narrow slit-like passages in the nasalairway, these passages become partially occluded when the nasal mucosais inflamed and congested, making the distribution of topicalpharmaceuticals to the nasal airway difficult.

SUMMARY OF THE INVENTION

It is thus an aim of the present invention to provide a delivery devicefor and a method of achieving a more optimally distributed deposition ofa substance, especially topical pharmaceuticals, in the nasal airway,particularly the posterior region of the nasal airway, and in particularthe anterior region of the nasopharynx where the adenoid and tubal ostiaare located.

Accordingly, the present invention provides a delivery device fordelivering a substance to the nasal airway of a subject, comprising: aclosure unit for causing the closure of the oropharyngeal velum of thesubject; and a delivery unit for delivering a gas flow entraining asubstance to one of the nostrils of the subject at such a drivingpressure as to flow around the posterior margin of the nasal septum andout of the other nostril of the subject, wherein the delivery unitcomprises a nosepiece which includes an outlet through which the gasflow is in use delivered to the one nostril and a sealing member forsealing the one nostril to the outlet such as in use to prevent theescape of the gas flow through the one nostril.

In one embodiment the substance comprises a dry powder.

In another embodiment the substance comprises liquid droplets.

Preferably, the particle size distribution of the substance isprincipally in the range of about 1 to 10 μm.

In one embodiment the substance contains a medicament, particularly forthe treatment of a nasal condition. In a preferred embodiment theparticle size distribution of the substance can include a smallerfraction of larger particles, typically in the range of about 10 to 30μm, and preferably in the range of about 20 to 30 μm.

In other embodiments the substance can be a cleansing agent, as a powderor liquid, for cleansing the nasal airway, or a liquid, which maypreferably contain a cleansing agent, for irrigating the nasal airway.By way of example, the delivery device could be used to administersaline or other solutions to the nasal airway to remove particles andsecretions, in particular from the posterior region of the nasal airway,which resulting solution could be analyzed for diagnostic or researchpurposes. In a preferred embodiment the particle size distribution ofthe cleansing or irrigating agents can include a fraction of largerparticles, particularly in relation to the mechanical action of theparticles.

The present invention also provides a method of delivering a substanceto the nasal airway of a subject, comprising the steps of: sealing oneof the nostrils of a subject to an outlet of a delivery unit such as toprevent the escape of a gas flow through the one nostril; closing theoropharyngeal velum of the subject; and delivering a gas flow entraininga substance through the outlet at such a pressure as to flow around theposterior margin of the nasal septum and out of the other nostril of thesubject.

In one embodiment the closure of the velum is achieved directly by theuse of an instrument for pressing against the velum to close the same ora bung for temporarily closing the opening behind the velum between thenasal airway and the oral cavity.

In a preferred embodiment the closure of the velum is achievedindirectly by the creation of a positive pressure in the oral cavity, ormore correctly a positive pressure differential between the oral cavityand the nasal airway, such as achieved on exhalation.

Preferably, the velum is closed simultaneously with the onset of thedelivery of the substance to the nasal airway.

In a preferred embodiment closure of the velum is achieved automaticallyby the subject exhaling against a flow resistor, which flow resistor maybe operably connected to a tubular section held between the lips of thesubject. The flow resistor can be configured to provide the requiredintra-oral positive pressure.

It has been established that flow rates of about 1 to 20 liters perminute, and particularly about 3 to 15 liters per minute, can be easilyachieved by a subject and that and a fairly constant air flow can bemaintained for up to 20 seconds depending on the flow rate. For sometreatment regimes, it is important that a stable flow of relatively highflow rate be maintained for a period of a few seconds, preferably 3 to10 seconds, in order to enable the substance to penetrate to the moreremote parts of the nasal airway.

In one embodiment the air flow of exhalation by a subject is used topower a mechanism which disperses the substance into a volume of air anddelivers that dispersed substance into the nasal airway.

Preferably, the mechanism is so arranged that the substance is deliveredinto the nasal airway after the velum has been closed or simultaneouslywith velum closure. In this respect, it will be understood thatbidirectional flow through the nasal cavities is possible only when thevelum is closed and that any substance delivered prior to closure of thevelum would undesirably be delivered to the lower airway or the gut.

Preferably, the release of the substance into the nasal airway istriggered by the air flow created on exhalation.

In a preferred embodiment a pressure-sensitive valve is utilized totrigger release of the substance when a predetermined flow rate has beendeveloped. It should be understood that control of the flow rate of thegas in which the substance is delivered is important, as this flow rate,along with the particle size distribution of the substance, are thesignificant factors determining the particle deposition efficiency.

In a preferred embodiment the pressure-sensitive valve is not openeduntil the subject has maintained a predetermined flow rate, and can beclosed when the flow rate drops below the predetermined flow rate so asto stop the delivery of the substance.

In a preferred embodiment, where medicament is delivered in a drivinggas, one or both of the timing and duration of the opening of thepressure-sensitive valve and the dose released are carefully controlledto ensure a standardized dosage.

In one embodiment, where the substance is released into a chamber and agas flow, in one embodiment the exhalation flow, is provided to inducethe mixing of a metered dose of the substance, the delivery of the gasflow can be prolonged to flush the nasal airway as this prolongedflushing does not effect the delivered dose. A mechanical device poweredby a hand-chargeable spring, pressurized air or similar, may be used toprovide the driving gas.

Regardless of the system employed, the flow characteristics can beoptimized to improve the deposition of the substance and the comfortfactor, such as to avoid an abrupt onset which is likely to inducewithdrawal reflexes.

Preferably, a metered dose of the substance is dispensed into a deliverychamber by a dosing mechanism. This dosing mechanism can be constructedin such a way as to allow for a gradual release of the substance. Thisgradual release will better enable the substance to be entrained by thegas flow and thereby improve delivery to all ventilated parts of thenasal airway, in particular in the contralateral nasal cavity.

In a preferred embodiment the exhalation air flow developed by thesubject, which closes the velum, provides the gas flow for entrainingthe substance and providing the bidirectional flow. This configurationis advantageous in that a separate driving gas flow need not bedeveloped.

Preferably, the nosepiece is configured to extend about 1 cm into theone nasal cavity so as to expand the valve region, a region locatedabout 2 to 3 cm within a nasal cavity which is usually the flow limitingregion, and reduce the resistance which may be high in the case of nasalinflammation.

The shape of the nosepiece can be tailored to suit specific needs. Forexample, the internal shape of the nosepiece may be optimized to promoteturbulence and achieve a more optimal dispersion of the substance.

The nosepiece may include a tight fitting nasal olive, which can aid thecreation of a suitable physiological gas flow. The olive may bedetachable such as to allow for other olives of the same or differentdimensions to be fitted. In the case of severe nasal obstruction, anasal olive can be introduced into the other nostril to reduceresistance and facilitate flow therethrough.

As mentioned above, a gas flow of at least 20 liters per minute caneasily be achieved by the delivery device. By providing a sufficientlyhigh gas flow, all parts, or at least a larger part, of the complexnasal airway can be penetrated by the substance. In one embodiment thedelivery device can include an indicator for indicating the magnitude ofthe gas flow.

The dimensions of the posterior passage and opening behind the nasalseptum are almost always larger than the opening in the flow resistor.Thus, it is only in very rare cases of complete occlusion of the outletnostril that the pressure in the posterior region of the nasal airwaywill approach the positive pressure in the oral cavity and jeopardizethe velum closure. In the case of severe obstruction, insertion of thenosepiece in the occluded nostril may reduce the resistance and allowsuccessful flushing.

After having flushed the nasal airway in one direction, the sameprocedure can be repeated from the other nostril. In this way both nasalcavities are irrigated in both directions. This is a unique feature ofthis device. This embodiment secures an improved distribution of thesubstance to all parts of the nasal mucosa, and in particular to theposterior region which is difficult to access using current techniques.

In a preferred embodiment, where the substance is in solid form, such asa powder, then a filter can be employed if high humidity represents aproblem for administration of the solid.

The substance can be a single compound or a mixture of compounds, whichcompounds can be in any suitable form, such as a powder form, asolution, or a suspension.

The substance can be any suitable substance for delivery to a human orin some cases an animal. The substance may be for delivery for action inany part of the nasal airway, or in any of the surrounding tissues ororgans. Also, the substance may be for delivery for action in a regionremote from the nasal airway.

Preferably, the substance is for delivery for subsequent action in anypart of the nasal airway, or in any of the surrounding tissues ororgans.

The substance may have a beneficial medical effect, which can include adiagnostic effect, a therapeutic effect, a prophylactic effect, and acleansing effect such as the removal of particles, crusts, secretions,debris, etc. Preferably, the substance has a therapeutic effect.

Preferably, the substance is a pharmaceutical. The pharmaceutical can beadmixed with any suitable carrier, diluent, excipient or adjuvant.

Preferably, the pharmaceutical is for the treatment of any one or moreof the abovementioned conditions. By way of example, the pharmaceuticalmay be for the treatment of any allergic and non-allergic inflammatorydisease.

Typical pharmaceuticals for administration include, but are not limitedto, steroids, anti-histamines, cromoglycates, anti-allergicpharmaceuticals, anti-inflammatory pharmaceuticals, anti-leucotriens,lactation promoters such as oxytocin, and antimigraine pharmaceuticals.

By achieving a more optimal delivery, the delivery device of the presentinvention improves the effect of topical pharmaceuticals in thetreatment of upper airway pathologies, such as hypertrophic adenoids andchronic sectretory otitis media.

Aside from pharmaceuticals, the device can also be used to irrigate orcleanse the nasal airway with saline or other solutions, preferablycontaining oils or herbs.

The device of the present invention can be tailored to suit particularneeds. For example, balloons or pop-up figures can easily be integratedto provide a semiquantitaive indication of the flow rate and to improvethe acceptability and ease of administration in small children.

Only in the rare circumstances when the nasal resistance is too high toachieve a gas flow through the nasal airway, even after attempting toexpand the nasal cavities, would insufflation be jeopardized. In thosecases, pre-treatment with decongestants may be necessary.

The delivery device may also be used as a nasal lavage means in thecollection of mediators and cells that originate from the nasal mucosafor, for example, diagnostic analysis or research purposes. In thisrespect, the mediators and cells can be expelled into a suitablecollecting vessel after the nasal airway has been exposed to a suitablesolution, such as a saline solution, for a sufficient period of time toensure sufficient transfer of the mediators and cells into the solution.This use of the device may require the use of a gas flow separate to theexhaled air flow as the flow used to flush the nasal airway. For thislavage purpose, use of the exhaled air may not be possible as the lowerairways may contain mediators, secretions and cells originating from thelower airways which would contaminate the nasal sample. For thisparticular use, and as indicated, the fluid escaping from the outletnostril may be collected in a vessel. Alternatively, the fluid escapingfrom the outlet nostril may be absorbed onto a filter for direct ordelayed analysis. Indeed, such filters and the like may even yield analmost immediate detection result of certain organisms, such asbacteria, viruses or mediators.

The delivery device of the present invention is advantageous for anumber of reasons.

Notably, the delivery device provides a very simple and efficient meansof delivering substances, such as pharmaceuticals, saline solutions,etc, into the nasal airway. In this respect, the device utilizes verysimple technology with few movable parts, making the device relativelyinexpensive to mass produce. In addition, the device of the presentinvention can be made in a disposable form, thus avoiding the need forthe delivered substance to include any preservatives.

The present invention also eliminates the need for the subsequentflushing or spraying methods that are associated with some of the priorart devices. However, for some applications it may still be desirable toperform a subsequent flushing or spraying operation.

The delivery device of the present invention is advantageous as, in use,the tight seal between the nosepiece and the one nostril ensures aprolonged penetration of the complex nasal airway, a bidirectional gasflow through the nasal cavities and deposition of the substance in thecontralateral nasal passage.

In accordance with the present invention, closure of the velum willnormally be maintained. The delivered gas flow enters one nasal cavity,passes beyond the posterior margin of the nasal septum, making a 180degree turn behind the posterior margin of the nasal septum, and passesout the other nasal cavity. This redirection of the gas flow results ina better deposition of substance, notably pharmaceuticals, to theposterior regions of the nasal turbinates and the nasal mucosa.

In addition, the bidirectional deposition of substances, typicallypharmaceuticals, and irrigation will also better reach all sinus ostiadue to the anatomic locations and orientation of the sinus ostia, whichcan improve sinus ventilation and drainage which is essential to treatsinusitis and frequently accompanies inflammation of the nasal mucosa.In this respect, the ostia and tubes to the ethmoidal and sphenoidalsinuses are located in the posterior region of the nasal airway and theuncinate projections covering the infundibulum, housing the maxillary,frontal and anterior ethmoid ostia, are tilted backwards. Furthermore,the driving positive pressure used will increase the deposition ofpharmaceuticals at the sinus ostia, the sinus tubes leading into thesinuses and even in the sinuses themselves.

In addition, the 180 degree redirection of the flow behind the nasalseptum particularly increases the deposition of substance on the roof ofthe nasopharynx where the adenoid is located and in proximity to thelocation of the tubal ostia to the auditory tubes connecting thenasopharynx and the middle ears. By way of example, steroids have beenshown to reduce the size of hypertrophic adenoids which are commonlyfound in paediatric subjects and can have a positive effect on secretoryotitis media. Deposition of topical decongestants closer to the tubalostia may also more efficiently decongest the auditory tubes and relievethe negative pressure in the middle ears which accompanies rhinitis andpredisposes paediatric subjects to secretory otitis media and theconsequential reduced hearing. Surgery for enlarged adenoids isfrequently performed in children and the improved medical therapy of thepresent invention should reduce the necessity for surgery.

A further advantage is that possible surplus substance, that is,substance which is not deposited, will be expelled out of thecontralateral nostril, where it may be collected, if desired, andconsequently not continue to the oral cavity and down into the gut as isthe case with many other delivery techniques. In this way, thediscomfort, and more importantly, the undesirable systemic exposure tothe substance, where the substance is a medicament, will be reduced.

Also, with the present invention, irrigation by saline or othersolutions can be performed more efficiently and with less spill anddiscomfort than the current techniques used for irrigation and flushingof the nasal airway.

Further, the present invention provides for simple and comfortableirrigation of the nasal mucosa with solutions, such as saline solutions,and other oils to remove secretions from the nasal mucosa and promotemucociliary function.

Still further, the present invention provides a simple and effectivemeans for the lavage of the nasal mucosa, such as to collect anddiagnose mucosal entities, such as bacteria, viruses, cell componentsand inflammatory mediators.

Still yet further, the exposure of the nasal mucosa to a positivepressure, particularly a dynamic positive pressure, will open thenarrow, and sometimes occluded, parts of the nasal passages, rather thancause a dynamic collapse which may happen during sniffing andinhalation. The dynamic positive pressure is at least 5 cm H₂O,preferably at least 50 cm H₂O, more preferably at least 100 cm H₂O,still more preferably at least 200 cm H₂O, yet more preferably 400 cmH₂O and still yet more preferably 500 cm H₂O. The dynamic positivepressure achieved by the present invention can be contrasted with thestatic pressure provided by the Valsalva procedure where there is noflow through the nasal airway.

In addition, the use of warm and humid air as the gas flow is likely tobe better tolerated and cause less irritation than room air or outdoorair, especially in cold climates.

Where the substance is a dry powder, then the humidity of the exhaledair may, in some instances, cause agglomeration of the powder.Naturally, this will depend on the properties of the powder and theconstruction of the device, in particular the dispersion chamber. Inorder to alleviate this specific problem, the surface properties of thepowder could be modified, or the device could include amoisture-absorbing element, typically containing a desiccant such assilica, disposed upstream of the dispersion chamber. In a preferredembodiment the moisture-absorbing element could be provided as a filterwhich acts as the flow resistor.

In a preferred embodiment, in order to ensure that agglomeration ofpowder would not impede the use of direct insufflation of warm, humidexhaled air, the delivery device comprises transfer means which createsa gas flow of drier air, such as atmospheric air, as the delivery flowto the nasal airway. Such transfer mean, which could be mechanical innature, utilises the energy of the exhaled air to drive the atmosphericroom air at the required flow rate, if necessary, to disperse thesubstance in the delivered air flow. In this embodiment agglomerationwill be prevented or at least reduced to the same level as currentlyexhibited by dry powder inhalers.

If desired, the distribution of the substance delivered to the nasalairway could be studied using standard techniques. By way of example,use could be made of acoustic rhinometry or coloured fluids. Thedistribution of the delivered substance could even be determined byvideo endoscopy. In addition, or in the alternative, distributionstudies could also be performed by using appropriate radioactivematerials and following the passage in the nasal cavities. The resultsof these studies could be used to optimise the flow rate, the shape ordimension of the device, in particular nosepiece geometry, and theparticle size distribution of the substance. The results of thesestudies could even be used to optimize subject acceptance.

As already indicated, the delivery device may include a balloon or asimilar pop-up device for indicating that the desired positive pressurehas been attained, which balloon or pop-up device may improve thecompliance in small children who are reluctant to use the device.

Alternatively, for particularly young children, the entraining gas flowcan be provided by the exhalation air flow of another person, such as aparent, or even by the use of a pump or the like, while the childcreates the required positive pressure in the oral cavity by inflating aballoon or pop-up device.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the present invention will now be describedhereinbelow by way of example only with reference to the accompanyingdrawings, in which:

FIG. 1 schematically illustrates the anatomy of the upper respiratorytract of a human subject;

FIG. 2 schematically illustrates a delivery device in accordance with afirst embodiment of the present invention;

FIG. 3 schematically illustrates a delivery device in accordance with asecond embodiment of the present invention;

FIG. 4 schematically illustrates a delivery device in accordance with athird embodiment of the present invention;

FIG. 5 schematically illustrates a modified delivery unit for theabove-described first to third embodiments of the present invention;

FIG. 6 schematically illustrates a delivery device in accordance with afourth embodiment of the present invention;

FIG. 7 schematically illustrates a delivery device in accordance with afifth embodiment of the present invention;

FIG. 8 schematically illustrates a delivery device in accordance with asixth embodiment of the present invention; and

FIG. 9 schematically illustrates a delivery device in accordance with aseventh embodiment of the present invention.

DETAILED DESCRIPTION

FIG. 2 illustrates a delivery device in accordance with a firstembodiment of the present invention.

The delivery device comprises an oral exhalation unit 20 and a substancedelivery unit 22. In this embodiment the oral exhalation unit 20 and thedelivery unit 22 are provided as separate components, but alternativelycould be detachably coupled, for example by means of Velcro™ fasteners,connected, for example by means of screws and/or rivets, or evenintegrally formed.

The oral exhalation unit 20 comprises a tubular section 24 and amouthpiece 26 attached to one end of the tubular section 24. Themouthpiece 26, which in use is gripped in the lips of a user, is formedseparately of the tubular section 24 to allow for replacement, but couldalternatively be integrally formed. In this embodiment the mouthpiece 26is a snap fit on the tubular section 24, but could equally be a screwfit. The tubular section 24 includes a flow resistor 28, in thisembodiment a fixed baffle plate, configured to provide a sufficientresistance to exhalation therethrough by a subject as to cause thegeneration of a positive pressure in the oral cavity of the subject andthe closure of the velum on exhalation by the subject. In alternativeembodiments the flow resistor 28 could be a movable member, such as abiased flap, a resilient membrane or a damped wheel.

The delivery unit 22 comprises a nosepiece 30, in this embodiment formedof a resilient material such as a polymeric material, for providing atight sealing fit in one of the nostrils of the subject, a medicamentsupply unit 32 for supplying a gas flow entraining medicament at apredetermined pressure sufficient to open a flow path beyond theposterior margin of the nasal septum when delivered into one of thenasal cavities of the subject, and a tubular section 34 coupling thenosepiece 30 and the medicament supply unit 32. In a preferredembodiment the nosepiece 30 can include an external olive or be shapedto cause the anterior region of the nasal cavity into which thenosepiece 30 is inserted to be enlarged. In a particularly preferredembodiment the nosepiece 30 can be shaped, for example by includingswirl-inducing projections, to provide the exiting gas flow with anoptimal flow pattern and particle size distribution. The nosepiece 30 isformed separately of the tubular section 34 to allow for replacement,but could alternatively be integrally formed. In this embodiment thenosepiece 30 is a snap fit on the tubular section 34, but could equallybe a screw fit. The medicament supply unit 32 can comprise an aerosolspray generator for generating an aerosol spray of liquid dropletscontaining medicament, such as provided by a pressurized metered doseinhaler, or a pressurized gas source for entraining a metered dose of adry powder containing medicament loaded thereinto, which powder couldalternatively be loaded into a compartment in the tubular section 34.

In use, a subject grips the mouthpiece 26 in his or her lips and fitsthe nosepiece 30 into one of his or her nostrils. The subject thenexhales through the mouthpiece 26, the flow of which exhaled air isresisted by the flow resistor 28 in the tubular section 24 such as todevelop a positive pressure in the oral cavity of the subject, with thepositive pressure being such as to develop a pressure differentialacross the velum sufficient to cause closure of the velum of thesubject. The applicant has established that a positive pressuredifferential between the oral cavity and the nasal airway of about 5cmH20 is required to maintain the velum in the closed position. Theapplicant has further established that a subject should be able tomaintain a flow rate of about 3 to 30 liters per minute for about 1 to20 seconds, with flow rates of about 10 to 20 liters per minute anddelivery times of about 2 to 5 seconds being considered as optimal.After closure of the velum, the medicament supply unit 32 is thenactuated to deliver a gas flow entraining medicament through thenosepiece 30 and into the nasal airway of the subject. As mentionedabove, this gas flow is at such a pressure as to open a communicationpath beyond the posterior margin of the nasal septum such that the gasflow flows through the one nasal cavity, around the posterior margin ofthe nasal septum, in effect being redirected through an angle of 180degrees, and out of the other nasal cavity. Again, as already described,this bidirectional flow provides for a much enhanced deposition of themedicament in the posterior region of the nasal airway.

In one modification, the medicament supply unit 32 can be omitted fromthe delivery unit 22, and instead a metered dose of dry powder loadedinto a compartment in the tubular section 34, with the delivery air flowbeing provided by another person, such as the parent of a paediatricsubject, blowing into the distal end of the tubular section 34.

FIG. 3 illustrates a delivery device in accordance with a secondembodiment of the present invention.

The delivery device comprises the oral exhalation unit 20 and thedelivery unit 22 of the above-described first embodiment, and an outletunit 36 for fitting to the other nostril of a subject to which thedelivery unit 22 is fitted.

The outlet unit 36 comprises a tubular section 38 and a nosepiece 40, inthis embodiment formed of a resilient material such as a polymericmaterial, attached to one end of the tubular section 38 for providing atight sealing fit in the other nostril of the subject. The nosepiece 40is formed separately of the tubular section 38 to allow for replacement,but could alternatively be integrally formed. In this embodiment thenosepiece 40 is a snap fit on the tubular section 38, but could equallybe a screw fit. As with the nosepiece 30 of the delivery unit 22, in apreferred embodiment the nosepiece 40 can include an external olive orbe shaped to cause the anterior region of the other nasal cavity intowhich the nosepiece 40 is inserted to be enlarged. The tubular section38 includes a flow resistor 41, in this embodiment a baffle plate,configured to provide a sufficient flow resistance to an exhalation flowtherethrough as to cause the generation of a dynamic positive pressurein the nasal airway. In a preferred embodiment the flow resistor 41 isadjustable to allow for adjustment of the level of the resistance andhence provide control of the dynamic pressure in the nasal airway. Inalternative embodiments the flow resistor 41 could be a movable member,such as a biased flap, a resilient membrane or a damped wheel.

In a preferred embodiment the outlet unit 36 includes an indicator forproviding at least one of a visual or audible signal on achieving apredetermined positive pressure upstream thereof, that is, in the nasalairway. Preferably, the indicator comprises a whistle. In this way, thesubject is provided with positive feedback of proper use of the device.

Use of the delivery device of this embodiment is the same as for theabove-described first embodiment. However, as mentioned above, by theprovision of the flow resistor 41 in the outlet unit 36 downstream ofthe outlet nostril of the subject, a positive dynamic pressure ismaintained in the nasal airway. This positive pressure advantageouslyacts to dilate the various ostia in the nasal airway, such as the sinusostia and the tubal ostia, and the associated tubes, namely the sinustubes and the auditory tubes, so as to promote the delivery ofmedicament thereto. Further, this positive pressure acts to improvedeposition on the adenoid which can often obstruct the tubal ostia, themiddle meatus which is a common location of nasal polyps, and the cleftto the olfactory cells.

FIG. 4 illustrates a delivery device in accordance with a thirdembodiment of the present invention.

The delivery device is very similar to that of the delivery device ofthe above-described second embodiment, and thus, in order to avoidunnecessary duplication of description, only the differences will bedescribed in detail, with like parts being designated by like referencesigns. This delivery device differs only in further comprising apressure sensor 43, in this embodiment a pressure-sensitive spring ormembrane, located in the tubular section 34 of the delivery unit 22downstream of the medicament supply unit 32, and a control unit 44coupled to the sensor 43 and the medicament supply unit 32.

The control unit 44 is configured to control the flow rate of thedelivery gas supplied by the medicament supply unit 32 in order tooptimize the particle deposition efficiency in the nasal airwayregardless of the degree of nasal congestion. As mentioned hereinabove,by maintaining an optimum flow rate in the nasal airway, the depositionefficiency of the medicament-containing particles is increased, referredto as the particle deposition efficiency. If, ordinarily, a flow rate ofabout 15 liters per minute is required to maximize the particledeposition efficiency, then in a congested nasal airway a lower flowrate, possibly 10 liters per minute, would be required and in an opennasal airway a higher flow rate, possibly 20 liters per minute, would berequired.

Operation of this delivery device is otherwise the same as that of theabove-described second embodiment.

FIG. 5 illustrates a modified oral exhalation unit 20 for the deliverydevices of the above-described embodiments.

This modified oral exhalation unit 20 differs in that the tubularsection 24 includes a lateral opening 45 upstream of the flow resistor28 and in further comprising, as an indicator, an inflatable FIG. 46connected to the lateral opening 45, which FIG. 46 when inflated assumesa prominent position in the field of vision of the subject. In FIG. 4,the FIG. 46 is shown inflated. By providing such a display feature,subject compliance, particularly in paediatric subjects, should beimproved. The oral exhalation unit 20 further comprises an inflationline 48 connected to the FIG. 46 which allows the FIG. 46 to be furtherinflated by another person, typically the parent of a paediatricsubject, or a pump. In an alternative embodiment, instead of beinginflatable, the FIG. 46 could be of any kind which is brought into aprominent position on exhalation by the subject, typically amechanically or electrically-operated figure. In a preferred embodimentthe FIG. 46 can be configured so as to be inflated on the subjectachieving an optimum exhalation flow rate. In this way, the FIG. 46 actsas an indicator.

Use of the delivery device of this embodiment is the same as that of theabovedescribed first embodiment. However, on exhaling through themouthpiece 26, the developed pressure causes the FIG. 46 to be inflatedand assume a prominent position in the field of vision of the subject.This appearance of the FIG. 46 is particularly appealing for paediatricsubjects as the fun element of inflating the FIG. 46 can alleviate anyunnecessary anxiety.

FIG. 6 illustrates a delivery device in accordance with a fourthembodiment of the present invention.

The delivery device comprises a chamber 50 which includes an inlet 52and an outlet 54, a mouthpiece 56 connected to the inlet 52 and anosepiece 58 connected to the outlet 54. The nosepiece 58 is configuredto provide a tight sealing fit in one of the nostrils of a subject. Thechamber 50 includes a flow resistor 60, in this embodiment a pluralityof baffle plates, and a medicament-receiving compartment 62 downstreamof the flow resistor 60 for containing a metered dose of a dry powdercontaining medicament to be delivered to the nasal airway of a subject.In this embodiment the nosepiece 58 is formed of a resilient materialsuch as a polymeric material. In a preferred embodiment the chamber 50may include a desiccant. In a preferred embodiment the flow resistor 60can be provided by a moisture-absorbing filter.

In use, a subject grips the mouthpiece 56 in his or her lips and fitsthe nosepiece 58 into one of his or her nostrils. The subject thenexhales through the mouthpiece 56, the flow of which exhaled air isresisted by the flow resistor 60 in the chamber 50 and the resistance ofthe nasal airway such as to develop a positive pressure in the oralcavity of the subject sufficient to cause closure of the velum. Theexhaled air, after passing the flow resistor 60, then entrains thepowdered medicament in the medicament receiving compartment 62, and thisair flow entraining medicament then passes through the nosepiece 58 intothe nasal airway of the subject. The exhaled air entering the nasalairway is at a pressure sufficient to open a communication path beyondthe posterior margin of the nasal septum such that the air flow flowsthrough the one nasal cavity, around the posterior margin of the nasalseptum, in effect being redirected through an angle of 180 degrees, andout of the other nasal cavity. Again, as already described, thisbidirectional flow provides for a much enhanced deposition of themedicament in the posterior margin of the nasal airway.

In a preferred embodiment the delivery device includes apressure-triggered valve, preferably located in the mouthpiece 56, whichis configured to open only when a predetermined positive pressure hasbeen developed by the exhalation of the subject, typically at a positivepressure of about 10 cm H₂O. This configuration advantageously avoidsthe possibility of medicament being delivered to the nasal airway withthe velum in the open position and thereby reduces the risk ofundesirably depositing medicament outside the nasal airway.

In another preferred embodiment, similarly to third-describedembodiment, the delivery device can include an outlet unit for providinga flow resistor downstream of the other nostril of the subject such asto maintain a positive dynamic pressure in the nasal airway.

FIG. 7 illustrates a delivery device in accordance with a fifthembodiment of the present invention.

The delivery device comprises an oral exhalation unit 70 through which asubject exhales to close his or her velum and a medicament delivery unit72 for supplying an air flow entraining medicament to the nasal airwayof the subject.

The oral exhalation unit 70 comprises a tubular section 74 and amouthpiece 76 attached to one end of the tubular section 74. Themouthpiece 76, which is gripped in the lips of the subject, is formedseparately of the tubular section 74 to allow for replacement, but couldalternatively be integrally formed therewith. In this embodiment themouthpiece 76 is a snap fit on the tubular section 74, but could equallybe a screw fit. The tubular section 74 includes a flow resistor 78, inthis embodiment a gearwheel, configured to rotate on exhalation by thesubject and yet provide sufficient resistance to the exhalation flow asto cause the generation of a positive pressure in the oral cavity of thesubject sufficient to maintain the required positive pressuredifferential between the oral cavity and the nasal airway and therebymaintain the velum in the closed position.

The delivery unit 72 comprises a tubular section 80 and a nosepiece 82,in this embodiment formed of a resilient material such as a polymericmaterial, for providing a tight sealing fit in one of the nostrils ofthe subject, attached to one end of the tubular section 80. Thenosepiece 82 is formed separately of the tubular section 80 to allow forreplacement, but could alternatively be integrally formed therewith. Inthis embodiment the nosepiece 82 is a snap fit on the tubular section80, but could equally be a screw fit. In a preferred embodiment thenosepiece 82 can include an external olive or be shaped to cause theanterior region of the nasal cavity, into which the nosepiece 82 isinserted, to be enlarged. In a particularly preferred embodiment thenosepiece 82 can be shaped, for example by including swirl-inducingprojections, to provide the exiting air flow with an optimal flowpattern and particle size distribution. The tubular section 80 includesan impeller 84 coupled to the gearwheel 78 in the tubular section 74 ofthe oral exhalation unit 70, such as to be rotated on rotation of thegearwheel 78 to draw air into the tubular section 80 and provide an airflow therethrough at a pressure sufficient to open the flow path beyondthe posterior margin of the nasal septum when delivered into one of thenasal cavities of the subject.

The delivery unit 72 further comprises a dispensing unit 86 fordispensing a metered dose of a dry powder containing medicament to thetubular section 80 upstream of the impeller 84. In this embodiment thedispensing unit 86 is manually actuated to supply a metered dose of drypowder containing medicament into the tubular section 80, but couldalternatively be configured to the driven by the gearwheel 78 so as toavoid the need for any manual intervention on the part of the subject.

In use, a subject grips the mouthpiece 76 in his or her lips and fitsthe nosepiece 82 into one of his or her nostrils. The subject thenexhales through the mouthpiece 76, the flow of which exhaled air isresisted by the gearwheel 78 such as to develop a positive pressure inthe oral cavity of the subject sufficient to cause the velum of thesubject to close. The exhaled air causes rotation of the gearwheel 78which in turn causes rotation of the impeller 84, and the rotation ofthe impeller 84 develops an air flow through the tubular section 80which entrains the metered dose of dry powder containing medicament anddelivers the same through the nosepiece 82 to the nasal airway of thesubject. As mentioned above, this air flow is at a pressure sufficientto open a communication path beyond the posterior margin of the nasalseptum such that the air flow flows through the one nasal cavity, aroundthe posterior margin of the nasal septum, in effect being redirectedthrough an angle of 180 degrees, and out of the other nasal cavity.Again, as already described, this bidirectional flow provides for a muchenhanced deposition of the medicament in the posterior region of thenasal cavity.

In a preferred embodiment the gearwheel 78 is configured such thatrotation thereof is prevented until a predetermined flow rate has beendeveloped which is sufficient to ensure that the entraining gas flowdeveloped by the impeller 84 is optimal. This configurationadvantageously ensures an optimal particle deposition efficiency andavoids the possibility of medicament being delivered to the nasal airwaywith the velum in the open position so as to reduce the risk ofundesirably depositing medicament outside the nasal airway.

FIG. 8 illustrates a delivery device in accordance with a sixthembodiment of the present invention.

The delivery device comprises a housing 90 for housing a blister packelement 92 which includes a plurality of blisters 94 therein, eachcontaining powder containing medicament, and a tubular section 96 incommunication with one of the blisters 94 when open, one end of whichtubular section 96 provides a mouthpiece 98 which in use is gripped inthe lips of a subject. The tubular section 96 includes an element 100movably disposed therein between a first, normally closed position and asecond, open position. In this embodiment the element 100 comprises apropeller or the like rotatably mounted on a threaded shaft and normallybiased to the closed position by a compression spring. The element 100is configured both to function as a flow resistor and a valve. In thisembodiment the element 100 is configured to move to themedicament-releasing open position by rotation along the threaded shaftagainst the bias of the compression spring, with the powder beingentrainable by an air flow only when the exhalation flow exceeds apredetermined flow rate. The flow rate, preferably in the range of about5 to 20 liters per minute, at which the powder containing medicament isentrained by the air flow is a function, in inverse relation, to thedriving pressure which is itself a function of the nasal resistance asdescribed hereinabove. As will be understood, this configurationadvantageously provides for an optimal particle deposition efficiency inreleasing the powder containing medicament at the optimal flow rate, andavoids the possibility of medicament being delivered to the nasal airwaywith the velum in the open position.

The delivery device further comprises a nosepiece 102, in thisembodiment formed of a resilient material such as a polymeric material,for providing a tight sealing fit in one of the nostrils of the subjectattached to the other end of the tubular section 96 downstream of theelement 100. The nosepiece 102 is formed separately of the tubularsection 96 to allow for replacement, but could alternatively beintegrally formed therewith. In this embodiment the nosepiece 102 is asnap fit on the tubular section 96, but could equally be a screw fit. Ina preferred embodiment the nosepiece 102 can include an external oliveor be shaped to cause the anterior region of the nasal cavity into whichthe nosepiece 102 is inserted to be enlarged. In a particularlypreferred embodiment the nosepiece 102 can be shaped, for example byincluding swirl-inducing projections, to provide the exiting air flowwith an optimal flow pattern and particle size distribution.

The delivery device further comprises a blister opening mechanism 104for opening the blister 94 in communication with the tubular section 96.In this embodiment the blister opening mechanism 104 is manuallyoperated by the subject prior to delivery.

In use, a subject grips the mouthpiece 98 in his or her lips and fitsthe nosepiece 102 into one of his or her nostrils. The subject thenexhales through the mouthpiece 98, the flow of which exhaled air isresisted by the element 100 until a predetermined flow rate has beenachieved. Once this predetermined flow rate has been achieved, at whichflow rate the velum is in the closed position, the element 100 is in theopen position and the exhaled airflow entrains the powdered medicamentin the blister 94 and delivers the same through the nosepiece 102 to thenasal airway. The driving pressure of this air flow is at a levelsufficient to maintain a communication path beyond the posterior marginof the nasal septum such that the air flow flows through the one nasalcavity, around the posterior margin of the nasal septum, in effect beingredirected through an angle of 180 degrees, and out of the other nasalcavity. Again, as already described, this bidirectional flow providesfor a much enhanced deposition of the medicament in the posterior marginof the nasal cavity.

In a preferred embodiment the delivery device includes a blister packadvancement mechanism, operated by movement of the mouthpiece 98, forrotating the blister pack element 92 such that another unused blister 94is located at the delivery position. In a particularly preferredembodiment the blister pack advancement mechanism can be coupled to theblister opening mechanism 104 such as automatically to open the blister94, and thereby avoid the need for any further intervention by thesubject.

In one modification, similarly to the above-described modification ofthe first embodiment as illustrated in FIG. 3, the delivery device caninclude an outlet unit for providing a flow resistor downstream of theother nostril of the subject such as to maintain a positive dynamicpressure in the nasal airway.

In another modification, the blister pack element 92 can be omitted andthe housing 90 instead provided with a chamber which is in communicationwith the tubular section 96 and into which a metered dose of dry powdercontaining medicament can be loaded. With this configuration, the powderin the chamber is entrained on the element 100 being driven to thesecond position and the blister pack advancement mechanism is configuredto meter a dose of powder containing medicament into the chamber onoperation thereof.

As will be understood, in essence, the present invention can be broadlybased on any dry powder inhaler, such as the Turbuhaler™ as manufacturedby AstraZeneca PLC, the Accuhaler™ as manufactured by Glaxo PLC or theTwisthaler™ as manufactured by Schering AG, where the usual mouthpieceis replaced by a nosepiece and a mouthpiece is provided in communicationwith the air inlet of the inhaler such as to utilize the air exhaled bya subject as the entraining delivery air.

FIG. 9 illustrates a delivery device in accordance with a seventhembodiment of the present invention.

The delivery device comprises a housing 110 and a tubular section 112extending through the housing 110, one end of which provides amouthpiece 114 which in use is gripped in the lips of a subject.

The tubular section 112 includes an element 116 movably disposed thereinbetween a first, normally closed position and a second, triggerposition. In this embodiment the element 116 comprises a propeller orthe like rotatably mounted on a threaded shaft and normally biased tothe closed position by a compression spring. The element 116 isconfigured to function as a flow resistor, a valve and a trigger for thedelivery of an aerosol spray into the tubular section 112 as will bedescribed in detail hereinbelow. In this embodiment the element 116 isconfigured to move to the medicament-releasing open position, byrotation along the threaded shaft against the bias of the compressionspring, only when the exhalation flow exceeds a predetermined flow rate.The flow rate at which the medicament is released, preferably in therange of about 5 to 20 liters per minute, is a function, in inverserelation, to the driving pressure which is itself a function of thenasal resistance as described hereinabove. As will be understood, thisconfiguration advantageously provides for an optimal particle depositionefficiency in releasing the medicament at the optimal flow rate, andavoids the possibility of medicament being delivered to the nasal airwaywith the velum in the open position.

The tubular section 112 further includes a nozzle block 117 forproviding an aerosol spray through the tubular section 112 along thelongitudinal axis thereof. As will be described in detail hereinbelow,the nozzle block 117 receives the valve stem 122 of an aerosol canister120.

The delivery device further comprises a known aerosol canister 120 usedto deliver metered volumes of a propellant, preferably ahydrofluoroalkane (HFA) propellant or the like, containing medicament,either as a suspension or as a solution. The aerosol canister 120comprises a main body 121 which contains a volume of propellant underpressure containing medicament, a valve stem 122 through which thepropellant containing medicament is in use delivered on relativemovement of the main body 121 and the valve stem 122, and a meteringvalve 124 for metering a predetermined volume of propellant containingmedicament to the valve stem 122 on movement thereof.

The delivery device further comprises a trigger mechanism 126 forrelatively moving the main body 121 and the valve stem 122 of theaerosol canister 120 to effect the delivery of a metered volume ofpropellant containing medicament through the nozzle block 117. In thisembodiment the trigger mechanism 126 comprises a resilient element 128for loading the main body 121 with an actuation force, and a leverassembly 130 coupled to the movable element 116 to cause the release ofthe actuation force provided by the resilient element 128 on movement ofthe movable element 116 from the closed position to the triggerposition.

The delivery device further comprises a nosepiece 132, in thisembodiment formed of a resilient material such as a polymeric material,for providing a tight sealing fit in one of the nostrils of the subject,attached to the other end of the tubular section 112 downstream of themovable element 116. The nosepiece 132 is formed separately of thetubular section 112 to allow for replacement, but could alternatively beintegrally formed therewith. In this embodiment the nosepiece 132 is asnap fit on the tubular section 112, but could equally be a screw fit.In a preferred embodiment the nosepiece 132 can include an externalolive or be shaped to cause the anterior region of the nasal cavity intowhich the nosepiece 132 is inserted to be enlarged. In a particularlypreferred embodiment the nosepiece 132 can be shaped, for example byincluding swirl-inducing projections, to provide the exiting air flowwith an optimal flow pattern and particle size distribution.

In use, a subject primes the trigger mechanism 126, grips the mouthpiece114 in his or her lips and fits the nosepiece 132 into one of his or hernostrils. The subject then exhales through the mouthpiece 114, the flowof which exhaled air is resisted by the movable element 116 until apredetermined flow rate has been achieved. Once this predetermined flowrate has been achieved, at which flow rate the velum is in the closedposition, the movable element 116 is in the open position, triggeringthe movement of the lever assembly 130 and hence the relative movementof the main body 121 and the valve stem 122 of the canister 120 todeliver a metered volume of propellant containing medicament to thenozzle block 117 to generate an aerosol spray of liquid dropletscontaining medicament through the nosepiece 132 to the nasal airway.This aerosol flow is at a pressure sufficient to maintain acommunication path beyond the posterior margin of the nasal septum suchthat the flow flows through the one nasal cavity, around the posteriormargin of the nasal septum, in effect being redirected through an angleof 180 degrees, and out of the other nasal cavity. Again, as alreadydescribed, this bidirectional flow provides for a much enhanceddeposition of the medicament in the posterior margin of the nasalcavity.

As will be understood, in essence, the present invention can be broadlybased on any breath-actuated pressurized metered dose inhaler, where theusual mouthpiece is replaced by a nosepiece and a mouthpiece is providedin communication with the air inlet of the inhaler such as both totrigger the triggering mechanism and utilize the air exhaled by asubject as the entraining delivery air.

Finally, it will be understood that the present invention has beendescribed in its preferred embodiments and can be modified in manydifferent ways without departing from the scope of the invention asdefined by the appended claims.

1-34. (canceled)
 35. A device for delivering a substance to the nasalairway of a subject, comprising: a flow resistor against which thesubject in use exhales; a nosepiece shaped and sized for insertion intoa nostril of the subject to create a fluid tight seal with the nostril,the nosepiece comprising an outlet through which a substance may bedelivered into the nasal airway of the subject; a substance supply unitin fluid communication with the outlet of the nosepiece; and anactuation mechanism operative, in response to the exhalation air flow,to cause substance in the substance supply unit to be entrained in a gasflow and delivered into the nasal airway of the subject; wherein thedevice is configured to create a positive pressure differential betweenthe oral cavity of the subject and the nasal airway of the subject whenthe subject exhales against the flow resistor, thereby indirectlyachieving closure of the oropharyngeal velum of the subject.
 36. Thedevice of claim 35, wherein the flow resistor is operably connected to atubular section configured to be held between the lips of the subject.37. The device of claim 35, wherein the flow resistor is operablyconnected to a mouthpiece.
 38. The device of claim 35, wherein theexhalation air flow provides the entraining gas flow for delivery of thesubstance.
 39. The device of claim 35, wherein the actuation mechanismis a dispersion mechanism operative to disperse a substance into theentraining gas flow.
 40. The device of claim 35, wherein an air flowseparate from the exhalation air flow entrains the substance fordelivery.
 41. The device of claim 40, wherein the separate air flow isprovided by atmospheric room air.
 42. The device of claim 41, whereinthe substance supply unit comprises a chamber comprising a propellant,and the separate air flow is provided by the propellant.
 43. The deviceof claim 35, further comprising: a pressure-triggered valve fluidlyconnected to the flow resistor, wherein the valve is configured to openwhen a predeterminable positive pressure is developed upon exhalation bythe subject.
 44. The device of claim 35, wherein the flow resistor isfluidly connected to the nosepiece and located upstream of the substancesupply unit.
 45. The device of claim 35, wherein the nosepiece is formedof a resilient material.
 46. The device of claim 35, wherein thenosepiece is configured to extend into a nasal cavity of the subject soas to expand the valve region of the nasal cavity of the subject. 47.The device of claim 35, further comprising: a positive pressureindicator or a flow rate indicator.
 48. The device of claim 35, whereinthe gas flow entraining a substance is delivered at a driving pressuresufficient to cause the gas to flow around the posterior margin of thenasal septum of the subject and out of the other nostril of the subject.49. A device for delivering a substance to the nasal airway of asubject, comprising: a delivery unit for delivering a substance to oneof the nostrils of the subject, wherein the delivery unit comprises anosepiece including an outlet through which the substance is in usedelivered to the one nostril and a sealing member for sealing the onenostril to the outlet, and an aerosol spray generator actuatable togenerate an aerosol spray containing a metered dose of the substancethrough the outlet to the nasal airway.
 50. The device of claim 49,further comprising: a flow resistor; wherein the device is configured tocreate a positive pressure differential between the oral cavity of thesubject and the nasal airway of the subject when the subject exhalesagainst the flow resistor, thereby indirectly achieving closure of theoropharyngeal velum of the subject.
 51. The device of claim 50, whereinthe flow resistor is operably connected to a tubular section configuredto be held between the lips of the subject.
 52. The device of claim 50,wherein the flow resistor is operably connected to a mouthpiece.
 53. Thedevice of claim 50, wherein the flow resistor is fluidly connected tothe nosepiece.
 54. The device of claim 49, further comprising: anactuation mechanism actuatable in response to oral exhalation by thesubject to actuate the aerosol spray generator to deliver a dose ofsubstance through the outlet to the nasal airway.
 55. The device ofclaim 49, wherein the delivery unit is configured to deliver the gasflow at a driving pressure which, with closure of the oropharyngealvelum of the subject, would be such as to cause the gas to flow aroundthe posterior margin of the nasal septum and out of the other nostril ofthe subject.
 56. The device of claim 49, further comprising: an outletunit comprising a nosepiece for fitting to the other nostril and a flowresistor for providing a flow resistance to the gas flow exiting theother nostril, so as in use to maintain a positive dynamic pressureupstream thereof.
 57. The device of claim 56, wherein the flow resistorof the outlet unit is adjustable to allow for adjustment of the flowresistance.
 58. The device of claim 50, wherein the delivery unitfurther comprises an indicator for providing at least one of a visual oran audible signal on exhalation by the subject against the flowresistor.
 59. The combination of the device of claim 49 and substance tobe delivered.
 60. A device for delivering a substance to the nasalairway of a subject, comprising: a delivery unit for delivering a gasflow entraining a substance to one of the nostrils of the subject,wherein the delivery unit comprises a nosepiece including an outletthrough which the substance is in use delivered to the one nostril and asealing member for sealing the one nostril to the outlet, and adispensing unit operable to dispense a metered dose of the substanceinto the gas flow when the gas flow has a predetermined flow rate. 61.The device of claim 60, further comprising: a flow resistor; wherein thedevice is configured to create a positive pressure differential betweenthe oral cavity of the subject and the nasal airway of the subject whenthe subject exhales against the flow resistor, thereby indirectlyachieving closure of the oropharyngeal velum of the subject.
 62. Thedevice of claim 61, wherein the flow resistor is operably connected to atubular section configured to be held between the lips of the subject.63. The device of claim 61, wherein the flow resistor is operablyconnected to a mouthpiece.
 64. The device of claim 60, wherein the flowresistor is fluidly connected to the nosepiece.
 65. The device of claim60, wherein the delivery unit further comprises a gas supply unit forsupplying a gas flow separate to an exhalation breath of the subject.66. The device of claim 65, further comprising: a control unit forcontrolling the gas supply unit such as to control the flow rate of thedelivered gas flow.
 67. The device of claim 60, wherein the deliveryunit is configured to deliver the gas flow at a driving pressure which,with closure of the oropharyngeal velum of the subject, would be such asto cause the gas flow to flow around the posterior margin of the nasalseptum and out of the other nostril of the subject.
 68. The device ofclaim 60, further comprising: an outlet unit comprising a nosepiece forfitting to the other nostril and a flow resistor for providing a flowresistance to the gas flow exiting the other nostril so as in use tomaintain a positive dynamic pressure upstream thereof.
 69. The device ofclaim 68, wherein the flow resistor of the outlet unit is adjustable toallow for adjustment of the flow resistance.
 70. The device of claim 61,wherein the delivery unit further comprises an indicator for providingat least one of a visual or an audible signal on exhalation by thesubject against the flow resistor.
 71. The combination of the device ofclaim 60 and substance to be delivered.
 72. A device for delivering asubstance to the nasal airway of a subject, comprising: a mouthpiecethrough which the subject in use exhales, such as to cause closure ofthe oropharyngeal velum of the subject; and a delivery unit comprising adelivery channel fluidly connected to the mouthpiece, a nosepiecefluidly connected to the delivery channel and includes an outlet throughwhich the exhaled air flow is in use delivered to the one nostril and asealing member for sealing the one nostril to the outlet, and adispersion mechanism powered by the exhaled air flow to disperse asubstance into exhaled the air flow.
 73. The device of claim 72, whereinthe delivery unit is configured to deliver the gas flow at a drivingpressure which, with closure of the oropharyngeal velum of the subject,would be such as to cause the gas to flow around the posterior margin ofthe nasal septum and out of the other nostril of the subject.
 74. Thedevice of claim 72, further comprising: an outlet unit comprising anosepiece for fitting to the other nostril and a flow resistor forproviding a flow resistance to the gas flow exiting the other nostril soas in use to maintain a positive dynamic pressure upstream thereof. 75.The device of claim 74, wherein the flow resistor of the outlet unit isadjustable to allow for adjustment of the flow resistance.
 76. Thedevice of claim 72, wherein the delivery unit further comprises anindicator for providing at least one of a visual or an audible signal onexhalation by the subject through the mouthpiece.
 77. The combination ofthe device of claim 72 and substance to be delivered.